A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinoma (HCC) is a well recognized complication of advanced NASH (non-alcoholic steatohepatitis). We sought to produce a rat model of NASH, cirrhosis and HCC.


METHODS
Adult Sprague-Dawley rats, weighing 250-300g, were fed a choline-deficient, high trans-fat diet and exposed to DEN in drinking water. After 16 weeks, the animals underwent liver ultrasound (US), sacrifice and assessment by microscopy, immunohistochemistry and transmission electron microscopy (TEM).


RESULTS
US revealed steatosis and focal lesions in 6 of 7. All had steatohepatitis defined as inflammation, advanced fibrosis and ballooning with Mallory-Denk bodies (MDB) with frank cirrhosis in 6. Areas of more severe injury were associated with anti-CK19 positive ductular reaction. HCC, present in all, were macro-trabecullar or solid with polyhedral cells with foci of steatosis and ballooned cells. CK19 was positive in single or solid nests of oval cells and in neoplastic hepatocytes. TEM showed ballooning with small droplet fat, dilated endoplasmic reticulum and MDB in non-neoplastic hepatocytes and small droplet steatosis in some cancer cells.


CONCLUSIONS
This model replicated many features of NASH including steatohepatitis with ballooning, fibrosis, cirrhosis and hepatocellular carcinoma. Oval cell proliferation was evident and the presence anti-CK 19 positivity in the cancer suggests oval cell origin of the malignancy.
de Lima
Vicência M R
VM
Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Enéas de Carvalho Aguiar No. 255, Instituto Central, # 9159, São Paulo 05403-000, Brazil.
Oliveira
Claudia P M S
CP
Alves
Venancio A F
VA
Chammas
Maria Cristina
MC
Oliveira
Ellen Pierre
EP
Stefano
José Tadeu
JT
de Mello
Evandro Sobroza
ES
Cerri
Giovanni Guido
GG
Carrilho
Flair José
FJ
Caldwell
Stephen H
SH
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D002455:Cell Division; D002796:Choline Deficiency / Q000473:pathology; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology / Q000648:ultrastructure; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D046529:Microscopy, Electron, Transmission; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography
D004041:Dietary Fats